1. Field of the Invention
The present invention relates to antibodies which are useful as .alpha..sub.v.beta..sub.3 integrin antagonists and as such are useful in pharmaceutical compositions and in methods for treating conditions mediated by .alpha..sub.v.beta..sub.3 by inhibiting or antagonizing .alpha..sub.v.beta..sub.3 integrins.
2. Background of the Invention
Integrins are a group of cell surface glycoproteins that mediate cell adhesion and therefore are mediators of cell adhesion interactions that occur in various biological processes. Integrins are heterodimers composed of noncovalently linked .alpha. and .beta. polypeptide subunits. Currently at least eleven different .alpha. subunits have been identified and at least six different .beta. subunits have been identified. The various .alpha. subunits can combine with various .beta. subunits to form distinct integrins.
The integrin identified as .alpha..sub.v.beta..sub.3 (also known as the vitronectin receptor) has been identified as an integrin that plays a role in various conditions or disease states including tumor metastasis, solid tumor growth (neoplasia), osteoporosis, Paget's disease, humoral hypercalcemia of malignancy, angiogenesis, including tumor angiogenesis, retinopathy, arthritis, including rheumatoid arthritis, periodontal disease, psoriasis and smooth muscle cell migration (e.g. restenosis). Additionally, it has been found that such integrin inhibiting agents would be useful as antivirals, antifungals and antimicrobials. Thus, antibodies that selectively inhibit or antagonize .alpha..sub.v.beta..sub.3 would be beneficial for treating such conditions.
It has been shown that the .alpha..sub.v.beta..sub.3 integrin binds to a number of Arg-Gly-Asp (RGD) containing matrix macromolecules, such as fibrinogen (Bennett et al., Proc. Natl. Acad. Sci. USA, Vol. 80 (1983) 2417), fibronectin (Ginsberg et al., J. Clin. Invest., Vol. 71 (1983) 619-624), and von Willebrand factor (Ruggeri et al., Proc. Natl. Acad. Sci. USA, Vol. 79 (1982) 6038-6041). Compounds containing the RGD sequence mimic extracellular matrix ligands so as to bind to cell surface receptors. However, it is also known that RGD peptides in general are non-selective for RGD dependent integrins. For example, most RGD peptides that bind to .alpha..sub.v.beta..sub.3 also bind to .alpha..sub.v.beta..sub.5, .alpha..sub.v.beta..sub.1, and .alpha..sub.IIb.beta..sub.IIIa. Antagonism of platelet .alpha..sub.IIb.beta..sub.IIIa (also known as the fibrinogen receptor) is known to block platelet aggregation in humans. In order to avoid bleeding side-effects when treating the conditions of disease states associated with the integrin .alpha..sub.v.beta..sub.3, it would be beneficial to develop selective antagonists of .alpha..sub.v.beta..sub.3 as opposed to .alpha..sub.IIb.beta..sub.IIIa. Antibodies selective for .alpha..sub.v.beta..sub.3 offer such an advantage.